Coagulation factors and the protein C system as determinants of thrombin generation in a normal population

Dielis, Arne W. J. H.; Castoldi, Elisabetta; Spronk, Henri M. H.; Oerle, René van; Hamulyák, Karly; Cate, Hugo Ten; Rosing, Jan

doi:10.1111/j.1538-7836.2007.02824.x

Cited by 213 publications

(242 citation statements)

References 32 publications

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“…3 Conceding the fact that no race matched controls were included in this study, a marked in vitro resistance to thrombomodulin was detected (as compared to historical controls) 7 indicating functional protein C resistance, which is in accordance with reported reduced protein C and S levels in SCD. 10 In interpreting these data several factors need to be considered.…”

supporting

confidence: 66%

No association of the hypercoagulable state with sickle cell disease related pulmonary hypertension

Beers¹,

Spronk²,

Cate³

et al. 2008

Haematologica

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No association of the hypercoagulable state with sickle cell disease related pulmonary hypertensionPulmonary hypertension (PHT) occurs in approximately 30% of adult patients with sickle cell disease (SCD) and is a risk factor for early death.1 Hypercoagulability has been linked to PHT in general and pulmonary artery thrombosis contributes to PHT progression regardless of its cause.2 Sickle cell patients are characterized by a hypercoagulable state 3 and both autopsy 4 and imaging studies 5 in sickle cell patients with moderate to severe PHT suggest a role of pulmonary artery thrombosis (albeit in situ thrombosis or pulmonary embolism) in SCD-related PHT. However, in a series of 78 consecutive adult sickle cell patients, large to medium sized pulmonary artery thrombosis was ruled out with VQ scintigraphy in 25 of 26 sickle cell patients with mostly mild PHT, suggesting that pulmonary artery thrombosis is probably a late event.6 Nonetheless, organized thrombi in small pulmonary arteries, especially in association with obliterating vessel wall changes, 4 may remain undetected with VQ scintigraphy. To further investigate the potential role of the hypercoagulable state in SCD related PHT sensitive markers of haemostasis were determined in sickle cell patients screened for PHT.Study design is extensively reported elsewhere. Consecutive outpatients were screened for PHT with trans-thoracic echocardiography with mild and moderate-severe PHT defined as a tricuspid regurgitant jet flow velocity (TRV) of 2.5-2.9 m/s and ≥3m/s, respectively. 1The study was carried out in accordance with the principles of the Declaration of Helsinki. Venous blood (3.2% citrate) was collected from the antecubital vein and platelet-poor plasma was prepared by two-step centrifugation (4000 rpm, 15 min followed by 10000 rpm, 5 min). Endogenous thrombin potential (ETP) was determined with the Calibrated Automated Thrombogram (Thrombinoscope BV, Maastricht, The Netherlands) in a 96-well plate fluorometer (Ascent Reader, Thermolabsystems OY, Helsinki, Finland). Thrombin generation was triggered with 1 pM recombinant relipidated tissue factor (rTF) and 4 µM phosphatidylserine/phosphatidylcholine/phosphatidylethanolamine vesicles in HEPESbuffered saline in presence and absence of thrombomodulin (kind gift from Prof. C. Hemker, Synapse BV, Maastricht, the Netherlands) added at a concentration that upon addition to normal pool plasma would reduce the ETP with 50%). No differences could be detected between any of the measured parameters between patients with and without PHT (Table 1). Furthermore, there was no significant correlation of any parameter to the TRV (data not shown). These findings are in accordance with recent studies in SCD 8 and β-thalassemia 9 (also characterized by a high incidence of PHT). Ataga et al. failed to show a significant difference in markers of hemostasis in a comparable number of sickle cell patients, even though there was a trend to higher TAT, F1.2 and D-dimer levels in PHT patients.8 However, they do not report on th...

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supporting

confidence: 66%

No association of the hypercoagulable state with sickle cell disease related pulmonary hypertension

Beers¹,

Spronk²,

Cate³

et al. 2008

Haematologica

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“…In contrast, there is a linear relationship between increasing levels of factor II and increased thrombin generation [32,33]. Finally, a recently published study has shown that, following activation with a high concentration of tissue factor, prothrombin is amongst the main determinants of total thrombin generation [34]. The available evidence therefore indicates that accumulation of factor II could be the primary determinant of thrombotic risk associated with frequent doses of PCC.…”

Section: Pccs and Thrombotic Risk: Pathogenesismentioning

confidence: 99%

Clinical review: Prothrombin complex concentrates - evaluation of safety and thrombogenicity

et al. 2011

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Prothrombin complex concentrates (PCCs) are used mainly for emergency reversal of vitamin K antagonist therapy. Historically, the major drawback with PCCs has been the risk of thrombotic complications. The aims of the present review are to examine thrombotic complications reported with PCCs, and to compare the safety of PCCs with human fresh frozen plasma. The risk of thrombotic complications may be increased by underlying disease, high or frequent PCC dosing, and poorly balanced PCC constituents. The causes of PCC thrombogenicity remain uncertain but accumulating evidence indicates the importance of factor II (prothrombin). With the inclusion of coagulation inhibitors and other manufacturing improvements, today's PCCs may be considered safer than earlier products. PCCs may be considered preferable to fresh frozen plasma for emergency anticoagulant reversal, and this is reflected in the latest British and American guidelines. Care should be taken to avoid excessive substitution with prothrombin, however, and accurate monitoring of patients' coagulation status may allow thrombotic risk to be reduced. The risk of a thrombotic complication due to treatment with PCCs should be weighed against the need for rapid and effective correction of coagulopathy.

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“…As an example, the European external assessment Three kinds of plasmas were chosen to cover the whole spectrum of thrombin generation measuring range, markedly hypocoagulable, normocoagulable and highly hypercoagulable, as compared to data obtained in healthy subjects under similar conditions [18,20]. For practical purposes it was decided for defective coagulation to supplement normal plasma with heparin.…”

Section: Discussionmentioning

confidence: 99%

Large external quality assessment survey on thrombin generation with CAT: further evidence for the usefulness of normalisation with an external reference plasma

Perrin

Depasse

Lecompte

et al. 2015

Thrombosis Research

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Calibrated Automated Thrombography (CAT) has been widely used to assess in vitro thrombin generation as an informative intermediary phenotype of coagulation. Interlaboratory exercises have documented a worrisome poor reproducibility. There are some data on the normalisation with an appropriate external reference plasma (RP). This multicentre study of the French-speaking CAT Club aimed at providing further evidence for the usefulness of such a normalisation

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Coagulation factors and the protein C system as determinants of thrombin generation in a normal population

Abstract: The lag time, ETP and peak height of thrombin generation depend on the levels of multiple coagulation factors and inhibitors. The specific assay determinants vary with the experimental conditions.

Cited by 213 publications

References 32 publications

No association of the hypercoagulable state with sickle cell disease related pulmonary hypertension

No association of the hypercoagulable state with sickle cell disease related pulmonary hypertension

Clinical review: Prothrombin complex concentrates - evaluation of safety and thrombogenicity

Large external quality assessment survey on thrombin generation with CAT: further evidence for the usefulness of normalisation with an external reference plasma

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